American society is experiencing an epidemic of obesity. Because of the key role of the hypothalamus in controlling body weight, the long-term objective of this research has been to examine arcuate nucleus hypothalamic genes involved in energy homeostasis. The proposed studies focus upon the hypothalamic melanocortinergic system which has become a focal point for basic research and drug development. That system contains alpha melanocyte-stimulating hormone (1-MSH) and melanocortin receptor (MCR) subtypes MC3R and MC4R. 1-MSH is a potent satiety-inducing factor that mediates its effects by binding and activating MC3R and MC4R. A continuing analysis of hypothalamic gene expression changes has identified ankyrin repeat and SOCS box containing protein 4 (Asb-4) as a very promising investigative target. Asb-4 is an important intracellular regulatory protein in CNS energy homeostatic circuits that is highly regulated in hypothalamic neurons. The proposed research is contained in four specific aims: 1) To examine alternative melanocortin signaling pathways. We hypothesize that MC3R and MC4R activate mitogen-activated protein kinase signaling pathways in addition to well- recognized cyclic AMP-dependent processes in hypothalamic neurons. 2) To determine the role of melanocortin signaling in regulation of c-Jun NH2-terminal kinase (JNK). We hypothesize that MC3R and MC4R, via Asb-4, regulate arcuate nucleus JNK activity. 3) To elucidate transcriptional regulation of Asb-4. We hypothesize that Asb-4 expression in the hypothalamus is regulated by the melanocortinergic peptide, 1-MSH. 4) To determine the role Asb-4 in feeding behavior. We hypothesize that ankyrin repeat and SOCS box containing protein 4 is a crucial intracellular protein in hypothalamic neurons. We hypothesize that directed overexpression of Asb-4 in hypothalamic proopiomelanocortin neurons will decrease food intake, increase energy expenditure and confe resistance to high fat diet-induced obesity. PUBLIC HEALTH RELEVANCE: American Society is experiencing an epidemic of obesity. The hypothalamis, an area in the brain that is essential in control of appetite and food intake, is the focus of these investigations. The proposal examines carefully the hypothalamic melanocortin signaling system, an important energy regulatory system that has postulated to effect appetite, energy expenditure, and glucose metabolism.